ESSAY ON CAUSES AND EFFECTS OF INSOMNIA

14 Copyright © SLACK Incorporated Insomnia Susan Mackie, MD; and John W. Winkelman, MD, PhD ABSTRACT Insomnia is frequently present in patients with a variety of psychiatric conditions. Both the Diagnostic and Statistical Manual of Mental Disorders , fifth edition and the Inter - national Classification of Sleep Disorders , third edition include definitions that emphasize symptoms of difficulty initiating or maintaining sleep in the face of adequate opportunity for sleep. Although insomnia has historically been thought of as merely a symptom of various psychiatric conditions, more recent research indicates that psychiatric patients with comorbid insomnia benefit from identification and specific treatment of the sleep disorder. This review provides an introduction to the changing definitions of insomnia disorder, discusses the complex relationship with psychiatric conditions, and outlines the most effective available treatment options for insomnia, including cognitive behavioral therapy and hypnotic agents. [Psychiatr Ann. 2015;45(1):14-18.] Susan Mackie, MD, is a Clinical Instructor in Medicine, Brigham and Women’s Hospital, Harvard Medical School. John W. Winkelman, MD, PhD, is the Chief, Sleep Disorders Clinical Research Program, Department of Psychiatry, Massachusetts General Hospital; and an As - sociate Professor in Psychiatry, Harvard Medi - cal School.

Address correspondence to John W.

Winkelman, MD, PhD, Sleep Disorders Clini - cal Research Program, 1 Bowdoin Square, 9th Floor, Boston, MA 02114; email: jwwinkel - [email protected].

John W. Winkelman discloses consulting fees from UCB Pharma, Insys, FlexPharma, and Merck & Co.; contracted research for UCB Pharma and Purdue; and expert testimony for Cantor Colburn. The remaining author has no relevant financial relationships to disclose.

doi: 10.3928/00485713-20150106-04 © Shutterstock A 22-year-old female presents and complains of difficulty with sleep - ing. She also endorses sadness, decreased interest in social activities, intru - sive thoughts about her role in her mother’s death, trouble concentrating, and passive suicidal ideation. The patient attributes these symptoms to her inability to obtain adequate sleep. She reports staying in bed for 12-14 hours each night but estimates only 4 hours total sleep time. This has af - fected her job performance; she is unable to complete tasks efficiently and is irritable when relating to colleagues. She often ru - minates during the day about how bad the night will be and has migrated her bedtime progressively earlier to attempt to achieve adequate sleep.

CME PSYCHIATRIC ANNALS • Vol. 45, No. 1, 2015 15 INSOMNIA Insomnia disorder is defined in the Inter - national Classification of Sleep Disorders , third edition (ICSD-3) as: 1) the patient reports difficulty initiating or maintaining sleep, or waking up too early; 2) sleep diffi - culties occur despite adequate opportunity and circumstances for sleep; and 3) the pa - tient describes daytime impairment that is attributable to the sleep difficulties. Patients must meet all three criteria in order to be diagnosed with insomnia. This first criterion represents a slight shift from the ICSD-2 , which included “unrefreshing sleep” in addition to difficulty initiating or maintaining sleep. Although clinically im - portant, “unrefreshing” or “nonrestorative” sleep has been notoriously difficult to con - sistently define and validate. Another change in the newer classifi - cation is the elimination of subtypes (eg, psycho-physiological, paradoxical, idio - pathic, insomnia due to a medical condi - tion, insomnia due to a mental condition, inadequate sleep hygiene) included in the ICSD-2 . The validity of these categories has been questioned, due to considerable overlap between groups and poor inter- rater reliability. 1 In clinical practice, these distinctions are rarely useful because they are either nearly impossible to identify (eg, paradoxical insomnia, in which the patient markedly misreports total sleep time) or practically interchangeable (eg, psycho- physiological insomnia and insomnia due to poor sleep hygiene, both of which war - rant similar behavioral interventions). The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM- 5)2 (Table 1 ) criteria for insomnia disor - der are similar to the ICSD . Changes be - tween the DSM-IV and DSM-5 reflect the same research advances that motivated the changes in ICSD . First, nonrestorative sleep is no longer by itself a complaint war - ranting a diagnosis of insomnia disorder.

Instead, dissatisfaction with sleep quality also requires 1 of the 3 cardinal symptoms of insomnia. Second, the DSM-5 removes the distinction between primary and co - morbid insomnia. As researchers have learned more about the relationship be - tween insomnia and psychiatric disorders, it has become increasingly clear that the relationship is often bidirectional. It is sel - dom clear that insomnia is merely second - ary to another disorder. Furthermore, vari - ous research studies suggest that insomnia itself should be addressed regardless of its comorbidity—a practice that may be facili - tated by the shift in terminology introduced in the DSM-5 . Pathophysiology Although it is considered a sleep dis - order, research has shown that the physi - ologic abnormalities characteristic of the disorder are present 24 hours per day. The crucial pathophysiologic feature of insom - nia is hyperarousal. 3 This is evidenced in a variety of physiologic domains including autonomic activation (increased heart rate, decreased heart rate variability); elevated stress hormones (eg, cortisol and norepi - nephrine); higher metabolic rate (increased VO 2 max [maximum rate of oxygen con - sumption] and brain metabolism); electro - encephalographic arousal (increased high- frequency beta activity); and behavioral evidence of decreased sleep propensity (in - creased latency to sleep during daytime nap opportunities). In parallel to these neurobiological al - terations, a common set of pathological cognitive-behavioral elements underlie insomnia in most patients. Frequently, insomnia is triggered in a susceptible in - dividual by a stressful life event—the pre - cipitant. This could be a social, medical, or psychological stressor that temporarily disrupts the normal sleep pattern. Acute insomnia is common in this setting and frequently resolves without treatment.

However, a subset of patients will go on to develop chronic insomnia despite resolu - tion of the initial precipitant. In this group, there are frequently both predisposing and perpetuating factors that maintain the un - satisfactory sleep pattern despite resolution of the precipitating circumstances. Predis - posing conditions may include a tendency toward rumination, poor coping skills, older age, or medical illness. Perpetuating factors are often behaviors undertaken by the patient as compensatory responses to the insomnia such as going to bed earlier, napping, and excessive thoughts about the need for sleep. These cognitive and behav - ioral patterns become counter-productive because they increase time in bed while alert and anxious, thereby creating a state of conditioned arousal in the bedroom that serves to further perpetuate insomnia.

Tools for Diagnosis The primary tools for diagnosis of in - somnia are clinical history and sleep dia - ries. Clinical history should focus on iden - tifying precipitants of insomnia as well as behavioral and cognitive features that may be perpetuating the disorder. A full psy - chiatric and medical history is an essential component of the workup of insomnia as comorbid disorders may be additional TABLE 1 DSM-5 2 Criteria for Insomnia Disorder • Dissatisfaction with sleep quantity or quality, associated with difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep • Sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning • Sleep difficulty occurs at least three nights per week • Sleep difficulty is present for at least 3 months • Sleep difficulty occurs despite adequate opportunity for sleep • Insomnia is not better explained by another sleep-wake disorder, a coexisting mental disorder, or the physiological effects of a substance CME 16 Copyright © SLACK Incorporated sources of sleep disruption and targets of therapy. In addition to history, sleep diaries are another important tool in the diagnosis of insomnia. Although insomniacs have a tendency to underestimate total sleep time, diaries can provide useful information about an erratic sleep schedule or exces - sive time in bed that may prove to be useful targets for behavioral intervention. Polysomnography is rarely required for the diagnosis of insomnia. The primary utility of this test is to exclude other sleep disorders that may be causing (or co-oc - curring with) the insomnia. Patients who report loud snoring, choking/gasping, or witnessed apneas should be studied to rule out sleep-disordered breathing. Those re - porting abnormal movements during sleep or dream-enactment behavior should be studied to rule out rapid eye movement be - havior disorder. Actigraphy is also seldom helpful clinically and has not been well validated in insomnia patients who may spend considerable time lying still in bed while awake.

Relationship with Other Psychiatric Disorders Insomnia is over-represented in a wide spectrum of psychiatric disorders. The most well described association is with mood disorders. This relationship is com - plex and bidirectional, as insomnia is not only a symptom of depression but also a predictor of it. In one meta-analysis study, the odds of new onset depression in pa - tients with insomnia compared to those without insomnia was 2.60 (confidence interval: 1.98-3.42). 4 The comorbidity of depression and in - somnia likely influences the presentation and the course of both disorders. For in - stance, depressed patients with insomnia tend to have a more severe form of de - pression compared to those without. 5 This group is also at a higher risk for adverse outcomes related to major depressive disor - der (MDD), particularly suicidal thoughts and behaviors. This association persists af - ter adjustment for depression severity and other psychiatric comorbidity. 3 With regard to characteristics of insomnia, it has com - monly been held that patients with MDD tend to have a propensity toward early morning awakenings as opposed to other types of insomnia. This association, how - ever, has not been substantiated in research studies. Instead, the distribution of insom - nia symptoms throughout the night seems to be similar to insomniacs without depres - sion. 6 It is true, however, that insomniacs with depression tend to have shorter total sleep time compared to those without de - pression 7—likely indicating a more severe form of insomnia. In bipolar depression, decreased sleep during the manic phase rarely meets crite - ria for insomnia due to perceived lack of need for sleep. However, recent research has shown that inter-episode bipolar pa - tients also sleep worse than normal con - trols, displaying impairment in clinical sleep variables and associated distress that frequently meets criteria for the diagnosis of insomnia. 8 Insomnia is also a frequent accompa - niment of other psychiatric disorders. In schizophrenic patients, the onset of psy - chosis is often associated with profound insomnia. Similarly, sleep difficulties may be a prodrome marking the imminent re - lapse of psychosis among treated patients. 9 The association between sleep disturbance and suicidal behaviors seen in depressed patients is also true in patients with schizo - phrenia, with an odds ratio = 12.7 noted in one study. 10 Because anxiety is a common predis - posing factor in insomnia, it is not surpris - ing that patients with anxiety disorders suffer disproportionately from insomnia.

Posttraumatic stress disorder (PTSD), in particular, is frequently characterized by the same hypervigilance that underlies insom - nia disorder. Furthermore, nightmares are common in this group and may be a trigger to sleep disturbance. It is likely that the re - lationship between insomnia and PTSD is bidirectional—sleep disturbance is not only a characteristic of PTSD but also a marker of increased vulnerability to a maladaptive stress response that generates PTSD. 11 Panic disorder is another anxiety disor - der that is frequently comorbid with insom - nia. This association may be due in part to nocturnal panic attacks, which have been reported in 58% of those with panic disor - der and may constitute a more severe form of the illness. 12 Although it is clear that noc - turnal panic attacks disrupt sleep and per - petuate insomnia, there is also evidence that sleep deprivation lowers the threshold for a panic response to a carbon dioxide chal - lenges. 13 As in other psychiatric disorders, there is likely a bidirectional causative re - lationship whereby nocturnal panic symp - toms provoke insomnia and lack of sleep in turn exacerbates panic disorder. In the past, insomnia was often viewed as a symptom of psychiatric disorders likely to resolve with treatment. However, as reflected in the new definitions de - tailed above, recent research has focused on insomnia and psychiatric disorders as distinct diagnostic entities with separate (albeit inter-related) characteristics and courses. Thus, in most cases, it is appropri - ate to undertake treatment for both disor - ders simultaneously.

TREATMENT There are two primary approaches to treatment of insomnia: cognitive behav - ioral therapy (CBT) and hypnotic medica - tions. Selection of a treatment approach should be made in collaboration with the patient. Some patients have a preference to avoid medications, while others aren’t able to make the time commitment or tolerate the temporarily increased fatigue required for CBT. In those who are willing and able, a combination of the two approaches is probably the most effective for long-term management.

Cognitive Behavioral Therapy Cognitive behavioral therapy for in - somnia (CBT-i) generally consists of 6-8 weekly sessions in which patients are taught to identify and rectify the unhelp - CME PSYCHIATRIC ANNALS • Vol. 45, No. 1, 2015 17 ful behaviors and cognitive patterns that perpetuate insomnia. A variety of strate - gies are taught in CBT-i, including sleep hygiene, relaxation techniques, and cogni - tive restructuring; however, the two com - ponents with proven efficacy are sleep re - striction and stimulus control. Stimulus control is based on principles of classical conditioning. In this model, the bedroom and the process of attempting to sleep become stimuli that produce anxiety and physiological arousal, thereby interfer - ing with sleep and perpetuating insomnia.

Accordingly, in CBT-i, the patient is di - rected to get out of bed when awake and unable to sleep in order to preserve the bed as a place for drowsiness/sleep. Sleep restriction is the other well-vali - dated intervention in CBT-i. Sleep diaries are crucial for successful implementation of this technique ( Figure 1 ). Initially, base - line diaries are used to determine the esti - mated total sleep time. The patient is given instructions to limit the total time in bed to the actual amount of time slept. Initially, total sleep time will decrease relative to Figure 1. Sleep diary example. TABLE 2 US Food and Drug Administration-approved Drugs for Treatment of Insomnia Drug Half-life (hours) Dose Range (mg) Side Effects Benzodiazepines • Estazolam • Temazepam • Flurazepam • Triazolam • Quazepam Benzodiazepine receptor agonists • Zaleplon • Eszopiclone • Zolpidem • Zolpidem ER • Zolpidem sublingual 10-24 4-18 47-100 2-3 25-84 1-2 5-6 2-3 2-3 2-3 1-2 7.5-30 15-30 0.125-0.25 7.5-25 5‐10 1-3 5-10 6.25-12.5 1.75-3.5 Common to all: residual sedation, com - plex sleep-related behaviors, antero - grade amnesia, falls (elderly) Orexin antagonist • Suvorexant 9-13 5-20 Headache, residual cognitive impairment, and sedation Melatonin agonist • Ramelteon 0.8-2 8 Dizziness, fatigue CME 18 Copyright © SLACK Incorporated baseline, but the increased sleep drive that ensues will over time facilitate faster sleep onset and better sleep maintenance. Such improvements help to reduce anxiety re - garding sleeplessness, increase confidence in the ability to fall and stay asleep, and lead to the reestablishment of a pattern of regular sleep. Time in bed is then gradually increased as long as difficulties with sleep initiation or maintenance do not return. In patients with psychiatric disorders, there are theoretical barriers that may in - terfere with successful implementation of CBT-i. For instance, lack of motivation in patients with mood disorders may interfere with adherence to the strict sleep sched - ule required in sleep restriction. Patients with PTSD or panic disorder may be un - able to suppress the arousal response using stimulus control due to persistent negative stimuli in the bedroom. In patients with bi - polar disorder, sleep restriction should be pursued with great caution due to risks of precipitating a manic episode. However, several studies have shown that the efficacy of CBT-i for insomnia symptoms is not dif - ferent between patients with and without depression, and may also produce thera - peutic benefit for the mood disorder. 14 In those with nightmares or nocturnal panic attacks, these symptoms should be concur - rently addressed because, when they are, CBT-i is also likely to be effective. 15 Hypnotics The most well-researched and com - monly used hypnotics bind to the benzodi - azepine site on gamma-aminobutyric acid- A (GABA-A) receptors ( Table 2 ). These include both the benzodiazepines and the newer benzodiazepine receptor agonists (BZRA). Although the newer agents are somewhat more selective for a subtype of the GABA-A receptor, practically this makes little difference. The choice of hyp - notic should be made based on the patient’s tolerance and preference as well as phar - macokinetic considerations. For instance, patients with exclusively sleep onset dif - ficulties may benefit from shorter-acting agents (eg, zolpidem, triazolam), whereas longer-acting agents (eg, lorazepam, eszopiclone) would be more appropriate for those with impaired-sleep maintenance.

If benzodiazepine agonists are ineffective, poorly tolerated, or contraindicated, alter - native treatment options include sedating antidepressants, melatonin agonists, atypi - cal antipsychotics, and antiepileptics. Several of the newer BZRA hypnotic medications have been studied specifically for use in patients with both insomnia and depression. Although evidence is conflict - ing regarding their efficacy to improve mood outcomes, it is clear that sleep and quality of life can be markedly improved by the use of hypnotic medications as adjuncts to antidepressants for the initial therapy of MDD with depression. 16 Fur - thermore, follow-up studies have shown no evidence of withdrawal or rebound in - somnia in such patients after the hypnotic is stopped. 17 CONCLUSION Clinicians treating psychiatric disorders should be comfortable making the diagno - sis of insomnia in their patients. The patient introduced in this case meets criteria for in - somnia as well as MDD. Although she is likely incorrect to attribute her mood disor - der solely to her sleep problems, a clinician would be equally incorrect to assume that her sleep problems are exclusively second - ary to the mood disorder. Including treat - ment for her insomnia will both address the suffering produced by sleeplessness and lead to a treatment plan that is amply supported by research evidence. Both a hypnotic medication and CBT-i would be helpful interventions alongside appropriate treatment of her depression.

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